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Leukaemias ‘re-programme’ themselves using epigenetic regulators

Some leukaemias are able to alter the proteins they express on the cell surface in order to evade cancer treatment. Targeted therapies based on these proteins then become ineffective and patients may relapse. One particular type of acute lymphoblastic leukaemia (ALL), referred to as MLL/AF4 ALL, is able to alter its genome so much that it completely switches to a different cancer.  But what turns this switch on?

The result of a collaboration between the Princess Máxima Center in the Netherlands, Newcastle University and the University of Birmingham (published in Blood) has now revealed that epigenetic dysregulation in ALL drives lineage switching (the complete immunophenotypic change from one cancer to another).

Pulling the ol’ switcheroo

ALL is a type of blood cancer that originates from lymphoid cells such as B cells or T cells. A chromosomal rearrangement, which forms the fusion gene MLL/AF4, is uniquely associated with Pro-B cell ALL. This subtype of ALL has a very poor prognosis because it can lineage switch to acute myeloid leukaemia (AML).

“By studying these switched MLL/AF4  leukaemias we showed that the switch can happen in blood cells throughout different stages of development in the bone marrow,” said Dr Simon Bomken, MRC Clinician Scientist, Honorary Consultant at Newcastle University and co-lead author of the paper. “Importantly, the switch can be a result of additional genetic changes that can be caused by chemotherapy itself. As a consequence, some leukaemias completely ‘re-programme’ themselves and switch identity from one cell type to another.”

The switch from lymphoid phenotype to myeloid phenotype results in relapse because the cancer cells lose the markers that immunotherapies target. The changes also mean that a new immune response needs to be generated against the myeloid phenotype. The scientists showed that this switch was due to dysregulated epigenetic control.

Using transcriptomics, the team revealed changes in gene expression and alternative splicing in lineage-switched relapses. Since some of these genes encoded transcription factors and epigenetic regulators, they looked at the packaging of DNA in these cells. There were major changes to how DNA was packaged across the whole genome, which then affected transcription factor binding. There were also less lymphoid transcription factor binding sites and more myeloid transcription factor binding sites that were accessible to replication machinery. As a result, genes associated with the lymphoid phenotype were downregulated, whereas genes associated with the myeloid phenotype were upregulated (figure 1). The subsequent preference for myeloid gene transcription caused the switch from ALL to AML.

Figure 1: Graphical abstract showing the mechanism of epigenetic dysregulation that drives myeloid gene expression. Top: In normal healthy cells, CHD4 (an epigenetic regulator that changes DNA packaging) is a part of a larger epigenetic complex called NuRD (nucleosome remodelling and deacetylation). NuRD binds the DNA and inhibits the expression of myeloid genes.Bottom: The mutation in the CHD4 gene means that the NuRD complex cannot bind this part of the DNA. This keeps the DNA ‘open,’ allowing replication machinery and transcription factors to bind for myeloid gene expression. Source: Published in Blood.

Now you see me, now you don’t

By changing cell type, the cancer becomes better at hiding from both the immune system and targeted immune therapies, such as CAR T-cells and bispecific T-cell engagers.

“When ALL cells switch their identity, the leukaemia becomes extremely difficult to treat. The fact that we now understand what the drivers of this switch are has important implications for our understanding of disease development but also the response of a child to therapy,” said Dr Olaf Heidenreich, co-lead of the study and Research Group Leader at the Princess Máxima Center for Paediatric Oncology. “This may enable us to identify the children who are at greatest risk of relapse and gives us the opportunity to adjust and personalize their treatment.”

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